Autoimmune regulator AIRE: Evidence for genetic differences between autoimmune hepatitis and hepatitis as part of the autoimmune polyglandular syndrome type 1

The mechanisms driving the immune-mediated destruction of hepatic tissues i n autoimmune hepatitis (AIH) are unknown. Recently the autoimmune regulator (AIRE), a gene associated with the development of the autoimmune polygland ular syndrome type I (APS-1), was cloned. About 15% to 20% of APS-1 patient s develop hepatitis. However, the role of AIRE mutations in AIH, primary sc lerosing cholangitis (PSC), and primary biliary cirrhosis (PBC) is not know n. To address this issue patients with AIH (n = 94), PSC (n = 60), and PBC (n = 30) were analyzed for the presence of mutations in exons 6, 8, and 10 of AIRE by single stranded conformation polymorphism and sequence analysis. Autoantibody patterns of patients with defects in AIRE were analyzed by in direct immunofluorescence, enzyme-linked immunosorbent assay and Western bl ot. Heterozygous mutations of AIRE were identified in 3 patients: a patient with PBC and a patient with AIH type I carried a R257X mutation, and a pat ient with AIH type 2, diabetes mellitus type I (IDDM), thyroid disease, and atrophic gastritis carried a G305S mutation in the first PHD ring finger d omain of the AIRE protein. None of the 3 patients with a defective AIRE all ele showed autoantibodies, which are known to associate with APS-1. These f indings show a differential genetic association of autoimmune liver disease s and hepatitis in APS-I, The subgroup of patients with heterozygous mutati ons in AIRE does not represent patients with an incomplete APS-1 syndrome. However, the Aire gene defect showed that genes involved in the induction o f immunologic tolerance provide candidates for etiologic factors in autoimm une liver diseases.